Petrus J.W. Naudé

Tumor necrosis factor receptor cross‐talk

Extensive research has been performed to unravel the mechanistic signaling pathways mediated by tumor necrosis factor receptor 1 (TNFR1), by contrast there is limited knowledge on cellular signaling upon activation of TNFR2. Recently published data have revealed that these two receptors not only function independently, but also can influence each other via cross‐talk between the different signaling pathways initiated by TNFR1 and TNFR2 stimulation. Furthermore, the complexity of this cross‐talk is also dependent on the different signaling kinetics between TNFR1 and TNFR2, by which a delicate balance between cell survival and apoptosis can be maintained. Some known signaling factors and the kinetics that are involved in the receptor cross‐talk between TNFR1 and TNFR2 are the topic of this review.

Lipocalin 2: Novel component of proinflammatory signaling in Alzheimer's disease

Alzheimers disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF‐α. TNF‐α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF‐α‐induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β‐amyloid toxicity. Moreover, Lcn2 silences a TNFR2‐mediated protective neuronal signaling cascade in neurons, pivotal for TNF‐a‐mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.—Naudé, P.J. W., Nyakas, C., Eiden, L. E., Ait‐Ali, D., van der Heide, R., Engelborghs, S., Luiten, P. G. M., De Deyn, P. P., den Boer, J. A., Eisel, U. L. M. Lipocalin 2: Novel component of proinflammatory signaling in Alzheimers disease. FASEB J. 26, 2811–2823 (2012). www.fasebj.org

Neutrophil gelatinase-associated lipocalin: A novel inflammatory marker associated with late-life depression

OBJECTIVE Systemic low graded inflammation has been identified as a possible biological pathway in late-life depression. Identification of inflammatory markers and their association with characteristics of depression is essential with the aim to improve diagnosis and therapeutic approaches. This study examines the determinants of plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL), which is selectively triggered by TNFα receptor 1 signaling within the central nervous system, and its association with late-life depressive disorder. METHODS Baseline data were obtained from a well-characterized prospective cohort study of 350 depressed and 129 non-depressed older persons (≥60years). Past 6month diagnosis of major depressive disorder (MDD) according to DSM-IV-TR criteria was assessed with the Composite International Diagnostic Interview (CIDI 2.0). Potential determinants of plasma NGAL included sociodemographic characteristics, lifestyle and psychiatric and physical comorbidity. RESULTS Plasma NGAL concentrations were significantly associated with age, male gender, smoking and waist circumference. Adjusted for these determinants, depressed patients had significantly higher NGAL plasma levels compared to non-depressed comparison group. Depressed patients who did not meet full criteria for MDD in the month before sampling (partially remitted) had lower plasma NGAL levels compared with those who did. Subjects with a recurrent depression had higher plasma NGAL levels compared to those with a first episode. NGAL levels were neither related with specific symptom profiles of depression nor with antidepressant drug use. CONCLUSION Adjusted for confounders, NGAL plasma levels are increased in depressed older persons, without any effect of antidepressant medication and age of onset.

Behavioural and psychological symptoms of dementia in Down syndrome: Early indicators of clinical Alzheimer's disease?

Behavioural and Psychological Symptoms of Dementia (BPSD) are a core symptom of dementia and are associated with suffering, earlier institutionalization and accelerated cognitive decline for patients and increased caregiver burden. Despite the extremely high risk for Down syndrome (DS) individuals to develop dementia due to Alzheimers disease (AD), BPSD have not been comprehensively assessed in the DS population. Due to the great variety of DS cohorts, diagnostic methodologies, sub-optimal scales, covariates and outcome measures, it is questionable whether BPSD have always been accurately assessed. However, accurate recognition of BPSD may increase awareness and understanding of these behavioural aberrations, thus enabling adaptive caregiving and, importantly, allowing for therapeutic interventions. Particular BPSD can be observed (long) before the clinical dementia diagnosis and could therefore serve as early indicators of those at risk, and provide a new, non-invasive way to monitor, or at least give an indication of, the complex progression to dementia in DS. Therefore, this review summarizes and evaluates the rather limited knowledge on BPSD in DS and highlights its importance and potential for daily clinical practice.

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

Significance TNF is known to play an important role in various neurodegenerative diseases. However, anti-TNF therapeutics failed in clinical trials of neurodegenerative diseases. This failure is most likely due to antithetic effects of the TNF receptors in the central nervous system, whereby TNFR1 promotes inflammatory degeneration and TNFR2 neuroprotection. Here we show that novel TNFR-selective therapeutics, i.e., a TNFR1 antagonist and a TNFR2 agonist, block neuroinflammation and promote neuronal survival in a mouse model of neurodegeneration related to Alzheimer disease as well as other neurodegenerative diseases. Most important, neuroprotection mediated by the TNFR1 antagonist is abrogated by simultaneous blockade of TNFR2 activation, revealing that neuroprotection requires TNFR2 signaling and uncover why anti-TNF drugs failed in treatment of neurodegenerative diseases. Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNFR2, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNFR2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

Analysis of cognition, motor performance and anxiety in young and aged tumor necrosis factor alpha receptor 1 and 2 deficient mice

TNF-α plays important functional roles in the central nervous system during normal physiological circumstances via intricate signaling mechanisms between its receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Although the roles of TNFR1 and TNFR2 in the diseased brain have received considerable attention, their functions on behavior and cognition in a non-inflammatory physiological aged environment are still unknown. In the present study we investigated the functional roles of TNFR1 and TNFR2 in learning and memory, motor performance and anxiety-like behavior via several behavioral and cognitive assessments in young and aged mice, deficient of either TNFR1 or TNFR2. Results from this study show that deletion of TNFR2 impairs novel object recognition, spatial memory recognition, contextual fear conditioning, motor performance and can increase anxiety-like behavior in young adult mice. Concerning the functions of TNFR1 and TNFR2 functioning in an aged environment, age caused memory impairment in spatial memory recognition independent of genotype. However, both young and aged mice deficient of TNFR2 performed poorly in the contextual fear conditioning test. These mice displayed decreased anxiety-like behavior, whereas mice deficient of TNFR1 were insusceptible to the effect of aging on anxiety-like behavior. This study provides novel knowledge on TNFR1 and TNFR2 functioning in behavior and cognition in young and aged mice in a non-inflammatory physiological environment.

Neutrophil Gelatinase-Associated Lipocalin and depression in patients with chronic heart failure.

Depression adversely affects prognosis in heart failure (HF) patients. Inflammation is indicated as potential biological pathway in this co-morbidity. Since increased levels of the cytokine Neutrophil Gelatinase-Associated Lipocalin (NGAL) are predictive for HF prognosis, and recently indicated in patients with major depression, this study examined the association of serum NGAL levels with symptoms of depression in patients with HF. Serum NGAL levels were measured in 104 patients with HF (left ventricular ejection fraction, LVEF⩽40). Depression, evaluated using the Beck Depression Inventory (BDI; total score, somatic and cognitive component), and the Hamilton Depression Rating scale (HAMD), at baseline and 12months follow-up, was associated with NGAL levels using mixed model analysis. Analyses were adjusted for demographics measures, disease severity indicators, inflammation, comorbidity and medication. Increased serum NGAL levels were significantly associated with depression measured by HAMD (baseline: r=0.25, p<.05) and BDI (baseline: r=0.22, p<.05; 12months: r=0.37, p<.01). This association remained significant after adjustment for covariates; age, sex, time, LVEF, and creatinine (HAMD, t=2.01, p=.047; BDI, t=2.28, p=.024). NGAL was significantly associated with somatic- (p=0.004), but not cognitive depressive symptoms (p=0.32). NGAL levels were associated with the experienced HF-related functional limitations (6min walk test), rather than the severity of cardiac dysfunction (LVEF). This study indicates that depression in patients with chronic HF is associated with elevated NGAL levels, independent of clinical severity of the underlying disease.

Relationship Between Physical Frailty and Low-Grade Inflammation in Late-Life Depression

To determine whether physical frailty is associated with low‐grade inflammation in older adults with depression, because late‐life depression is associated with physical frailty and low‐grade inflammation.

The role of neutrophil gelatinase associated lipocalin (NGAL) as biological constituent linking depression and cardiovascular disease

Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.

Neuropsychiatric Disturbances in Alzheimer's Disease: What Have We Learned from Neuropathological Studies?

Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.